RADIATION HORMESIS; POSSIBILITIES AND CHALLENGES.

BY OGBONNA CHIAGOZIE ADAOMA

2001/111312

SUBMITTED TO DEPARTMENT OF MEDICAL RADIOGRAPHY AND RADIOLOGICAL SCIENCES,FACULTY OF HEALTH

SCIENCES,COLLEGE OF MEDICINE,UNIVERSITY OF NIGERIA,ENUGU CAMPUS.

IN PARTIAL FULFILLMENT OF THE COURSE RG 592.

SUPERVIS0R:MRS NWOGU .U SEPTEMBER 2008

TITLE PAGE

RADIATION HORMESIS;

POSSIBILITIES AND CHALLENGES

DEDICATION

This is to my Father,God.

ACKNOWLEDGEMENT

A big thank you to my parents,again.

Chizu you are the best sister in the whole world!

To all of you that have been here when it really really mattered,THANK

YOU!

TABLE OF CONTENT

TITLE PAGE

DEDICATION

ACKNOWLEDGEMENT

ABSTRACT

TABLE OF CONTENT

, CHAPTER ONE

INTRODUCTION

BACKGROUND OF STUDY

CHAPTER TWO

2.1 POSSIBILITIES

2.2 EXPERIMENTAL EVIDENCE

2.3 EPIDEMIOLOGICAL EVIDENCE

CHAPTER THREE

3.1 CHALLENGES

CHAPTER FOUR

CONCLUSION

REFERENCES

CHAPTER ONE

1.1 INTRODUCTION

All living organisms evolved and live in a sea of ionizing radiation both internal and

external but much of it is internal. It is a general belief that low doses of ionizing

radiation produce detrimental effect proportional to the effect produced by high level

radiation (S.M Javad, 2001). Despite the fact that high doses of ionizing radiation are

detrimental, substantial data from both human and experimental animals show that

biological functions are stimulated by low dose radiation (Luckey, 1980). The word

horinesis is derived from the Greek word "hormaein which means to "excite". It has

loni been known that many popular substances such as alcohol and caffeine have mild

stimulating effect in low doses but are detrimental or even lethal in high doses. In the

early 19407s,C.Southam and his co- worker J. Erlish found that despite the fact that

high concentrations of Oak bark extract inhibited fungi growth, low doses of this

agent stimulated fungi growth. They modified Starling's word hormone to horrnesis to

describe stimulation induced by low doses of an agent that can not be predicted by the

extrapolation of detrimental or lethal effect undivided by high doses of the same

agent.

During the 1950's Luckey, a pioneer researcher in radiation hormesis, indicated that

low doses dietary antibiotics caused a growth surge in livestock. Later he found that

horinesis could be induced effectively by low doses of ionizing radiation. In 1980, the

first complete report on radiation horinesis was published (Luckey TD 1980). In this

report, he reviewed numerous articles regarding radiation hormesis. Since the first

reports, 3000 papers have been published on the benefits of low doses of ionizing

radiation.

1.2 BACKGROUND OF STUDY.

The concept of radiation hormesis is usually applied to physiological benefits from

low LET radiation in the range of 1-5OcGy total absorbed closed (Macklis 1991). It is

widely believed that radiation biology in the future will be focused on bimolecular and

genetic implications, problems of damage and repair and connected problems such as

radiation hormesis and radioadaptive response (S.M Javad, 200 1). A literature search

revealed much information suggesting that large and small doses evoke opposite

effects;

: Hippocrates, Similia similibus curentur or "likes are cured by likes",

: Paracelsus, the father of infinitesimal doses, "the dose makes the poison",

: Hahnemann, "Drugs have a dynamic effect when used in small doses"

: Cannon, "Adaptation to perturbations is the basis for homeostatis"

: Selye, "The General Adaptation SyndroneVand Ardnt. Schultz, "poisons are

stimulants in small doses". These were supported by the remarkable findings of Richet

4

(1906). He understood the oligodynamic action of metals as proposed by Nageli

( 1 893): very dilute solutions of metallic ions are toxic. Richet quantified the toxic

effect by using serial dilutions of several metallic ions. He found that each metal ion

exhibited a threshold and was stimulatory at subharmful doses. They linked out

antibiotic response to classic science. Nevertheless, the threshold dose response has

became the key model in toxicology and pharmacology. Many physiologic functions

show radiation hormesis: growth and visual acuity, learning and memory fecundity,

immune competence, cancer mortality and average lifespan (luckey 1990: 1993). The

effect of chronic, whole body exposure to low doses of ionizing radiation upon four

physical function show radiation homesis.

CHAPTER TWO

2.1 POSSIBILITIES

In the early days of x-rays and radioactivity, it was generally believed that ionizing

radiation has numerous beneficial effects. It was claimed that blindness might be

cured by x-rays. Ladies corsets contained radium! Drinking mineral water containing

radium was very popular. People went to spas to drink radioactive water or stayed for

hours in caves to be irradiated by ionizing radiation. (For a review, see Wolff 1992).

Between 1925 and 1930, over 400,000 bottles of distilled water containing radium

226 and radium 228 were sold. It was advertised that some mixtures could treat over

150 diseases, especially lassitude and sexual impotence (Macklis 1990). It is estimated

that the collective skeletal radiation dose of victims of such radioactive medicine may

had exceeded 350Sv by the time the user died (M'acklis 1991). Gradually people find

that the improper use of ionizing radiation could lead to many complications and

harmful effects. Later in 1927, Herman J.Muller a Nobel Prize winner, found that x-

rays are mutagen and that there is a linear relationship between mutation rate and

6

dose. He proposed that mutations which are induced by radiations (or other mutagens)

are mostly detrimental. When it was generally accepted that excessive radiation may

be harmful, the first regulations for dose limits were introduced. Despite

carcinogenicity of x-rays, was observed as early as 1902 (kathren 1996) the first

radiation protection limits suggested in 1925 and for three other decades, these limits

were based on the concept of a tolerance dose (Muller 1928). Surprisinly, until the end

of world war 1 I, ionizing radiation was considered a great scientific miracle. After the

war, the development of nuclear power changed this great miracle into radiophobia.

At that time, people became afraid of even very small doses of ionizing radiation.

After the atomic bomb explosions in Hiroshima and Nagasaki, studies concerning life

span of atomic bomb survivors showed a liner relationship between cancer mortality

and high doses of radiation (Pollycove, 1998). The United Nation's Scientific

Committee on the Effects of Atomic Radiation (UNSCEAR), then proposed the linear

no-threshold (LNT) theory in 1958 (UNSCEAR, 1958). According to LNT theory;

7

I . The effect of low doses of ionizing radiation can be estimated by linear

extrapolation from effects observed by linear extrapolation from effects observed by

high doses.

2. There is no safe dose because even very low doses of ionizing radiation produce

some biological effect. In 1959 the international commission on radiation protection

(ICRP) adopted the LNT theory. (ICRP 1959).

The results of many investigations do not support the LNT theory. Furthermore,

several studies including Cohen's studies of the relationship between environmental

radon concentrations and lung cancer even contradict this theory and clearly suggest a

hormetic effect.

2.2 EXPERIMENTAL EVIDENCE

Cancer Prevention

Bhattarchargee in 1996 showed that when the mice preirradiated with just adapting

doses of IcGyldaji for 5days (without a challenge dose),thymic lymphoma was

includes in 16% of the animals (Bhattarachargee 1996). Interestingly when

preirradiated mice were exposed to a 2cGy challenge dose, thymic Iymphona was

included again in 16% of the animals. However, the challenge dose alone induced

thymic lymphoma in 46% of the mice. From these results, it can be concluded that

the low doses preirradiation possibly cancel the induction of thymic lymphoma by the

2Gy challenge doses. In 1996, Azzam and his colleagues showed that a single

exposure of C3H 1 OT112 cells to doses as low as 0.IcGy reduces the risk of neoplastic

transformations. They suggested that a single low dose at background or occupational

exposure levels may reduce cancer risk. Recently, Redpath and his co-workers have

confirmed the findings of Azzam and his co-workers (Azzam et al, 1996). To test the

9

generality of the observations of Azzam and his colleagues, they used the Hela x skin

j'ibroblast human hybrid cell. Using a similar experimental protocol, they

demonstrated a significantly reduced transformation frequency for adapted to

unirradiated cells (pooled data from four separate experiments). In addition, recently

Mitchel and his co-workers in Canada have indicated that a low dose preirradiation

(IOcGy, O.5GyIh) modifies latency for radiation induced myeloid levkamia in CBAIH

mice after exposure (mitehel et a1 1999). They showed that the latent period for

development of acute myeloid leukamia (AML) was significantly increased by the

prior low radiation dose. Interestingly, according to T.D Luckey, one third of all

cancer deaths are premature one preventable by low-level ionizing radiation (Luckey

1994, 1997).

Survival Rate

In 1996, Yonezawa and his colleagues indicate that when 21-ICR mice were exposed

to 8GY of X-rays, about 30% of the animals survived 30 days the irradiation.

10

However, when mice preirradiated with 5 cGy of X-rays, the survival rate increased to

about 70% (Yonezawa et al. 1996)

2.3 EPIDEMIOLOGICAL EVIDENCE

Although radiation hormesis data are still incomplete, extensive epidemiological

studies have indicated that radiation hormesis really exist. A brief review on this

irrefutable evidence is as follows:

Japanese studies

1-According to UNSCEAR report (1994), among A-bomb survivors from Hiroshima

and Nagazalti who received doses lower than 200mSv, there was no increase in the

number of total cancer death. Mortality caused by leukemia was even lower in this

population at doses below 100 msv than age-matched control cohorts.

2-Mifune (1992) (Mifune et al. 1992) and his co-workers indicated that in a spa area

(Misasa), with an average indoor radon level of 35 B ~ I ~ ~ , the lung cancer incidence

was about 50% of that in a low-level radon region. Their result also showed that in the

1 1

above mentioned high background radiation area; the mortality rate caused by all

types of cancer was 37% lower.

3-According to Mine et a1 (1981), among A-bomb survivors from Nagasaki, in some

age categories, the observed annual rate of deat is less than what is statistically

expected.

4-Kumatori and his colleagues (Kumatori et al. 1980) report that according to their 25

year follow up study of Japanese fishermen who were heavily contaminated by

plutuniuim (hydrogen bomb test at Bikini ), no one died from cancer.

Background Radiation Studies

1-In an Indian study, it was observed that in areas with a high-background radiation

level, the incidence of cancer and also the mortality rate due to cancer was

significantly lesser than similar areas with a low background radiation level (Nambi

and Soman 1987).

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2-In a very large scale study in U.S.A, it was found that the morality rate due to all

malignancies was lower in states with higher annual radiation dose (Frigerio 1976).

3-In a large scale Chinese study, it was showed that the mortality rate due to cancer

was lower in an area with a relatively high background radiation (74,000 people),

while the control group (78,000 people) who lived in an area with low background

radiation had a higher rate of mortality (Wei L1990).

4-In the U.S.A., it was indicated that significantly, the total cancer mortalityis

inversely correlated ,with background radiation dose (Cohen BL 1993).

Nuclear Power Plant studies

1-111 a Canadian survey the mortality caused by cancer at nuclear power plants was

58% lower than the national average (Abbat et al. 1983).

2-In U.K also it was indicated that cancer frequency among nuclear power plant

workers was lower than the national average (Kendal et al. 1992).

CHAPTER THREE

CHALLENGES

During the last decade, there has been a concerted effort to determine whether the

concept of horinesis is real and generalizable as well a toxicologically and biologically

significant.To this end, there has been developed a rigorous a priori process to assess

and quantitatively evaluate possible hormetic dose-response relationships, estimate the

frequency of hormetic dose responses in the toxicological literature and estimate

which toxicological model occurred more frequently in the peer reviewed literature.

(Calabrese, 2002, 2003; Calabrese & Baldwin 2001a, 2003b). Our activities have

shown that horinetic dose responses are more common than the traditional

toxicological threshold model, can be generalized well by model, endpoint and

chemical class, and display a predicable set of quantitative dose-response features in

terms of magnitude and width of the stimulatory response. In short, the hormesis

14

inodel clearly outperforms either of the other two competitive models in fair head-to-

head competition (Calabrese & Baldwin, 200 1 b, 2003a)

But despite the obvious superiority of the hormetic model over the linear model at low

dose and the threshold inodel, toxicological thinking has so far been hesitant to accept

and apply it. The reasons for this reluctance to change are complex but can be traced

in large part to the fact that toxicology has been, primarily, an applied discipline with

the laudable goal of protecting health. Faced with a huge number of compounds to be

tested, toxicologists therefore streamlined their processes to reduce the number of

animals used per dose and the number of doses per experiment. A typical

toxicological examination derives study-specific LOAELs (lowest observed adverse

effect levels) and NOAELs (no observed adverse effect levels) from experimental data

using animal models in which only 2-4 different doses of the compound under scruity

are used- plus control groups of course. With the goal of deriving a NOAEL with the

fewest doses possible, it becomes immediately obvious that any insights into what is

15

happening in the doinain below the NOAEL cannot be obtained by such studies.

Furthermore, it takes many more doses-and, accordingly, animals and time-to get a

clear picture of the doinain in which hormesis takes place.

It is important to recognize that the dose-response relationship is the most important

aspect in.toxicology, around which all research and teaching is centred. It is therefore

both troubling and of great concern that this field could have accepted a flawed

toxicological dose-response model but also built an entire education and regulatory

edifice on it with serious repercussions for

detailed re-examination of this historical

academia, industry and the public. A

blind spot in toxicology reveals a

complicated web of interacting factors that led to the demise of the hormesis

hypothesis: first and foremost the principle concern with high-does affects limited

study designs and difficulties in assessing the typically modest hormetic reponses

especially within the framework of weak study designs. The field also saw bitter

historical rivalries between traditional and homeopathic medicine, the latter regarding

hormesis-that is, the Arndt-Schulz Law-as a central explanatory feature. This has

resulted in a lack of intellectual leadership by those supporting a "hormetic

perspective and a lack of governmental funding of the hormesis concept during the

formative years of toxicological development from the 1930s onwards (Calabrese &

Baldwin, 2000a-e). All these factor contributed to today's situation, in which

hormesis, despite growing supportive evidence mainly from biomedical research, has

only a spotty and peripheral role in toxicology.

But, if accepted, the.hormetic dose-response model could have a large impact on risk

assessment in many significant ways. It would not even require a complete rethinking

in toxicology as the hormetic response is a normal component of the traditional dose-

response relationship. And because hormetic dose response are similar for

carcinogenic and non-carcinogenic agents, it has the potential to harmonize risk

assessment procedures for carcinogen and non-carcinogens alike, which have so far

been treated differently.

17

But what is particularly important is the fact that the hormetic dose response occurs in

the observable zone of the experimental data. This means that we would not need to

extrapolate experimental data far into the realm of the uncertain as is done at present

in cancer risk assessment, which relies on the animal-derived LNT prediction. Thus,

we could replace this scientifically questionable practice with a verifiable procedure.

In fact, as the hormesis hypothesis can actually be tested with the available data, for

the first time in the modern history of cancer risk assessment, we would be able to rely

on a verifiable d0s.e-response model and not depend on unverifiable extrapolations of

animals' data to estimates actual risk to humans.

The most fundamental change in the disk assessment process would be the adoption of

the hormetic model as the default risk assessment tool replace the outdated LNT

model for carcinogens and the threshold model for non-carcinogens. Because the

number of dosages used in most bioassays, especially those used by government

agencies such as the US National Toxicology program, is modest (3-4 dosages), there

18

is little like hood that the respective models sufficiently differ from each other in their

predictive power. Thus, regardless of which dose-response model is selected as the

default, it will be used in most cases. Typically, the selection of a default model has

been driven by concern of the regulatory agencies to err on the side of safety, given all

the uncertainties associated with extrapolating over many magnitudes.In addition to

being guided by a protectionist public health philosophy, the selection of a default

model also assumes objective superiority over its competitors both theoretically and

based on experimental or empirical data. Substantial evidence now exists to support

the scientific advantage of the hormetic model over its competitors. Given the

situation, it would seem that the time has come to re-examine which model should be

selected as the default in environmental risk assessment.

Perhaps the most exciting aspect of adopting the hormetic hypothesis in

environmental risk assessment is that it would allow the field to move forward

scientifically. It would replace the present status of compelling society by acting on

19

the basis of assumptions that cannot be adequately tested by a new risk assessment

procedure that can be realistically evaluated with its results displayed visibly in the

observable zone. This would be a major first step in placing "modern" environmental

risk assessment on similar level with other type of "health insurance", where risk

estimates are based on data that do not require extraordinary extrapolations and where

the findings create a heightened sense of confidence.

CHAPTER FOUR

CONCLUSION

Finally, radiation hormesis is in a special class of hormetics. The very concept of

horinesis .has important implications for the field of clinical medicine. The dose-

response relationships for medical agents commonly display the same hormetic dose-

response relationships as their toxic counterparts. Many agents such as antibacterial,

antifungals, antivirals and tumour. Fighting drugs display horrnetic dose responses.

The clinical significance of this has only recently begun to dawn on the medical

coin~nunity although it was recognized as early as the mid 40's for antibiotics such as

streptomycin The consequences for human health are quite serious. An excess is

harmful. Small amounts are needed for essential physiologic functions.

Supplementation is usual for populations. living in a partial deficiency. Irradiation

supplementation promises increased quality of life and a new plane of health for

2 1

people in the 21" century. A broader recognition of the hormetic dose response in the

wider biomedical domain has the potential to usher in a vast array of new

opportunities for understanding basic biological processes and to exploit such

knowledge in the development of new product and the improved treatment of patients.

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